The objective of the proposed research is to determine the etiologic, biochemical mechanism leading to pulmonary emphysema. Available information strongly suggests that damage to lung elastin by neutrophil or other elastases is the initial event in experimental emphysema. The experiments described will elucidate the dynamics (fate, distribution, flux) of neutrophil elastase in the normal lung, both animal and human, and in the diseased lung in experimentally induced lung disease and in human patients with emphysema. The role of alpha-1 antitrypsin and other protease inhibitors in the lungs and mucous secretions in controlling these mechanisms will be determined. Elastase dynamics will be studied in animal models exposed to elastases, cadmium and bacterial pneumonia, as well as cigarette smoke. The development or predisposition to experimental emphysema will be studied in these models, as well as in animals exposed to cigarette smoke. The studies will determine the biochemical, physiologic, ultrastructural and pathologic characteristics leading to emphysema with emphasis on the role of the elastase-elastin interaction. Lung elastin will be specifically studied to determine the role of cleavage of elastin precursors and the microfibrillar and amorphous components of mature elastin. Finally, the identification of the cleavage products of lung elastin in blood and lung secretions will be investigated by immunologic techniques to determine if an early diagnostic test can be developed.